Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, OR 97006, USA.
Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, OR 97006, USA.
Physiol Behav. 2019 Jul 1;206:166-174. doi: 10.1016/j.physbeh.2019.04.002. Epub 2019 Apr 2.
Early overnutrition disrupts leptin sensitivity and the development of hypothalamic pathways involved in the regulation of metabolism and feeding behavior. While previous studies have largely focused on the development of neuronal projections, few studies have examined the impact of early nutrition on hypothalamic synaptic physiology. In this study we characterized the synaptic development of proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH), their sensitivity to leptin, and the impact of early overnutrition on the development of these neurons. Electrophysiology recordings were performed in mouse ARH brain slices containing POMC-EGFP neurons from postnatal age (P) 7-9 through adulthood. We determined that pre- and postsynaptic components of inhibitory inputs increased throughout the first 3 weeks of the postnatal period, which coincided with a decreased membrane potential in POMC neurons. We then examined whether chronic postnatal overnutrition (CPO) altered these synaptic connections. CPO mice exhibited increased body weight and circulating leptin levels, as described previously. POMC neurons in CPO mice had an increase in post-synaptic inhibitory currents compared to controls at 2 weeks of age, but this effect reversed by the third week. In control mice we observed heterogenous effects of leptin on POMC neurons in early life that transitioned to predominantly stimulatory actions in adulthood. However, postnatal overfeeding resulted in POMC neurons becoming leptin-resistant which persisted into adulthood. These studies suggest that postnatal overfeeding alters the postsynaptic development of POMC neurons and induces long-lasting leptin resistance in ARH-POMC neurons.
早期营养过剩会破坏瘦素敏感性和参与代谢和摄食行为调节的下丘脑途径的发育。虽然以前的研究主要集中在神经元投射的发育上，但很少有研究检查早期营养对下丘脑突触生理学的影响。在这项研究中，我们描述了下丘脑弓状核（ARH）中 proopiomelanocortin（POMC）神经元的突触发育、它们对瘦素的敏感性以及早期营养过剩对这些神经元发育的影响。在包含 POMC-EGFP 神经元的小鼠 ARH 脑切片中进行了电生理学记录，这些神经元来自出生后第 7-9 天到成年期。我们确定，在出生后的前 3 周内，抑制性输入的前突触和后突触成分增加，这与 POMC 神经元的膜电位降低相吻合。然后，我们检查了慢性新生期营养过剩（CPO）是否改变了这些突触连接。如前所述，CPO 小鼠表现出体重增加和循环瘦素水平升高。与对照组相比，CPO 小鼠的 POMC 神经元在 2 周龄时后突触抑制性电流增加，但这种效应在第 3 周时逆转。在对照组中，我们观察到瘦素对 POMC 神经元在生命早期的异质作用，这种作用在成年期转变为主要的刺激作用。然而，新生期过度喂养导致 POMC 神经元对瘦素产生抗性，这种抗性持续到成年期。这些研究表明，新生期过度喂养改变了 POMC 神经元的突触后发育，并诱导了 ARH-POMC 神经元的长期瘦素抵抗。
